The HDAC inhibitor AR42 interacts with pazopanib to kill trametinib/dabrafenib-resistant melanoma cells in vitro and in vivo.
Studies focused on the killing of activated B-RAF melanoma cells by the histone deacetylase (HDAC) inhibitor AR42. Compared to other tumor cell lines, PDX melanoma isolates were significantly more sensitive to AR42-induced killing. AR42 and the multi-kinase inhibitor pazopanib interacted to activate: an eIF2?-Beclin1 pathway causing autophagosome formation; an eIF2?-DR4/DR5/CD95 ... pathway; and an eIF2?-dependent reduction in the expression of c-FLIP-s, MCL-1 and BCL-XL. AR42 did not alter basal chaperone activity but increased the ability of pazopanib to inhibit HSP90, HSP70 and GRP78. AR42 and pazopanib caused HSP90/HSP70 dissociation from RAF-1 and B-RAF that resulted in reduced 'RAF' expression. The drug combination activated a DNA-damage-ATM-AMPK pathway that was associated with: NF?B activation; reduced mTOR S2448 and ULK-1 S757 phosphorylation; and increased ULK-1 S317 and ATG13 S318 phosphorylation. Knock down of PERK, eIF2?, Beclin1, ATG5 or AMPK?, or expression of I?B S32A S36A, ca-mTOR or TRX, reduced cell killing. AR42, via lysosomal degradation, reduced the protein expression of HDACs 2/5/6/10/11. In vivo, a 3-day exposure of dabrafenib/trametinib resistant melanoma cells to the AR42 pazopanib combination reduced tumor growth and enhanced survival from ~25 to ~40 days. Tumor cells that had adapted through therapy exhibited elevated HGF expression and the c-MET inhibitor crizotinib enhanced AR42 pazopanib lethality in this evolved drug-resistant population.
Mesh Terms:
Angiogenesis Inhibitors, Animals, Antineoplastic Combined Chemotherapy Protocols, Autophagosomes, Blotting, Western, Cell Line, Tumor, Cell Survival, Drug Resistance, Neoplasm, Drug Synergism, Eukaryotic Initiation Factor-2, Histone Deacetylase 6, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Imidazoles, Kaplan-Meier Estimate, Male, Melanoma, Mice, Nude, Microscopy, Fluorescence, Oximes, Phenylbutyrates, Pyridones, Pyrimidines, Pyrimidinones, RNA Interference, Signal Transduction, Sulfonamides, Xenograft Model Antitumor Assays
Angiogenesis Inhibitors, Animals, Antineoplastic Combined Chemotherapy Protocols, Autophagosomes, Blotting, Western, Cell Line, Tumor, Cell Survival, Drug Resistance, Neoplasm, Drug Synergism, Eukaryotic Initiation Factor-2, Histone Deacetylase 6, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Imidazoles, Kaplan-Meier Estimate, Male, Melanoma, Mice, Nude, Microscopy, Fluorescence, Oximes, Phenylbutyrates, Pyridones, Pyrimidines, Pyrimidinones, RNA Interference, Signal Transduction, Sulfonamides, Xenograft Model Antitumor Assays
Oncotarget
Date: Mar. 07, 2017
PubMed ID: 28146421
View in: Pubmed Google Scholar
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